Novel MYH11 and ACTA2 mutations reveal a role for enhanced TGF¦Â signaling in FTAAD

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• 作者：Marjolijn Renard^a ; ¹ ; ^{Marjolijn.Renard@ugent.be} ; Bert Callewaert^a ; ¹ ; Machteld Baetens^a ; Laurence Campens^a ; Kay MacDermot^b ; Jean-Pierre Fryns^c ; Maryse Bonduelle^d ; Harry C. Dietz^e ; ^f ; Isabel Mendes Gaspar^g ; Diogo Cavaco^g ; Eva-Lena Stattin^h ; Constance Schrander-Stumpelⁱ ; Paul Coucke^a ; Bart Loeys^a ; ^j ; Anne De Paepe^a ; Julie De Backer^a
• 关键词：Thoracic aortic aneurysm ; Myosin heavy chain 11 ; Smooth muscle ¦Á-actin ; TGF¦Â signaling
• 刊名：International Journal of Cardiology
• 出版年：2013
• 出版时间：10 May, 2013
• 年：2013
• 卷：165
• 期：2
• 页码：314-321
• 全文大小：1350 K

文摘

Background

Thoracic aortic aneurysm/dissection (TAAD) is a common phenotype that may occur as an isolated manifestation or within the constellation of a defined syndrome. In contrast to syndromic TAAD, the elucidation of the genetic basis of isolated TAAD has only recently started. To date, defects have been found in genes encoding extracellular matrix proteins (fibrillin-1, FBN1; collagen type III alpha 1, COL3A1), proteins involved in transforming growth factor beta (TGF¦Â) signaling (TGF¦Â receptor 1 and 2, TGFBR1/2; and SMAD3) or proteins that build up the contractile apparatus of aortic smooth muscle cells (myosin heavy chain 11, MYH11; smooth muscle actin alpha 2, ACTA2; and MYLK).

Methods and result

In 110 non-syndromic TAAD patients that previously tested negative for FBN1 or TGFBR1/2 mutations, we identified 7 ACTA2 mutations in a cohort of 43 familial TAAD patients, including 2 premature truncating mutations. Sequencing of MYH11 revealed an in frame splice-site alteration in one out of two probands with TAA(D) associated with PDA but none in the series of 22 probands from the cohort of 110 patients with non-syndromic TAAD. Interestingly, immunohistochemical staining of aortic biopsies of a patient and a family member with MYH11 and patients with ACTA2 missense mutations showed upregulation of the TGF¦Â signaling pathway.

Conclusions

MYH11 mutations are rare and typically identified in patients with TAAD associated with PDA. ACTA2 mutations were identified in 16 % of a cohort presenting familial TAAD. Different molecular defects in TAAD may account for a different pathogenic mechanism of enhanced TGF¦Â signaling.